This project is focused on identifying a surface metalloprotease, specifically expressed on sperm or eggs, that is essential for conception and developing a contraceptive agent that acts as a specific inhibitor of this metalloprotease. Metalloprotease inhibitors are currently used as drugs and more are being developed to treat a variety of human disorders. In our research we have recently made two discoveries that serve as the basis for each of the two aims of this proposal. Specific Aim 1. Develop a metalloprotease inhibitor as a contraceptive agent that blocks the function of sperm-specific ADAM proteases (testases). We have found that there is a subfamily of the ADAM family of proteins called the testases. These proteins have a metalloprotease consensus active site, indicating they have enzyme activity; their expression is confined to the testis. We will test the hypothesis that testases have a required role, or perhaps more than one role, in sperm development, maturation or in sperm function. We will then proceed toward development of a metalloprotease inhibitor that blocks testase activity and can be used as a contraceptive agent. Specific Aim 2. Develop a metalloprotease inhibitor as a contraceptive agent that blocks sperm- egg fusion. We also found that there is a metalloprotease, apparently required for mammalian sperm-egg fusion, present on either the sperm or the egg surface. In Aim 2 we propose to identify that metalloprotease activity. We will test if it is an ADAM protease or matrix metalloprotease (MMP) on the egg or the sperm. If the protease is a sperm ADAM (i.e., a testase), Aims 1 and 2 will intersect. Once a unique metalloprotease is identified, we will test for tissue specificity and proceed toward development of a drug that will act as an inhibitor for that specific metalloprotease activity.